PT - JOURNAL ARTICLE AU - Jun Guo AU - Xian Li AU - Heidi Shallow AU - Jianmin Xu AU - Tonghua Yang AU - Hamid Massaeli AU - Wentao Li AU - Tao Sun AU - Grant N. Pierce AU - Shetuan Zhang TI - Involvement of Caveolin in Probucol-Induced Reduction in hERG Plasma-Membrane Expression AID - 10.1124/mol.110.069419 DP - 2011 May 01 TA - Molecular Pharmacology PG - 806--813 VI - 79 IP - 5 4099 - http://molpharm.aspetjournals.org/content/79/5/806.short 4100 - http://molpharm.aspetjournals.org/content/79/5/806.full SO - Mol Pharmacol2011 May 01; 79 AB - The human ether-à-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier K+ current (IKr) important for cardiac repolarization. Dysfunction of the hERG channel causes long QT syndrome (LQTS). Although diverse compounds reduce the hERG current (IhERG) by blocking the channel, probucol, a cholesterol-lowering drug that causes LQTS, reduces IhERG by decreasing plasma-membrane hERG protein expression. Here, we investigated the mechanisms of probucol effects on hERG expression levels. Our data demonstrate that probucol accelerated the degradation of mature hERG channels, which associated with caveolin-1 (Cav1) in hERG-expressing HEK cells. In human embryonic kidney (HEK) cells without hERG expression, probucol promoted endogenous Cav1 degradation. In hERG-expressing HEK cells, overexpression of Cav1 enhanced, whereas knockdown of Cav1 impeded, probucol-induced reduction of mature hERG channels. Thus, probucol reduces hERG expression through accelerating Cav1 turnover. The effects of probucol on Cav1 and hERG result from probucol's cholesterol-disrupting action, because low-density lipoprotein (LDL), a potent cholesterol carrier, effectively prevented probucol-induced reduction of IhERG in hERG-expressing HEK cells and of IKr in neonatal rat cardiomyocytes. Our data provide evidence that targeting hERG-interacting protein caveolin represents a novel mechanism for drugs to decrease hERG expression and cause LQTS.